ARID1A Mutations Research Articles

Phase IIa Study of PLX2853 in Gynecologic Cancers With Known ARID1A Mutation and Phase Ib/IIa Study of PLX2853/Carboplatin in Platinum-Resistant Epithelial Ovarian Cancer.

The Bromodomain and Extra-Terminal (BET) domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small-molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all four BET family members. We conducted a multicenter and open-label study with two parallel arms: a phase IIa study of PLX2853 monotherapy in patients with advanced gynecologic malignancies with an ARID1A mutation and a phase Ib/IIa combination study of PLX2853 plus carboplatin in women with platinum-resistant OC. The primary objectives were safety and tolerability for phase Ib and efficacy for both phase IIa portions. Thirty-four of 37 enrolled patients completed at least one post-baseline response assessment. Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a best overall response of partial response (PR), 5 (35.7%) had stable disease (SD), and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable patients on the combination arm, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD. This study confirmed the safety profile of PLX2853 and demonstrated the feasibility of combination with carboplatin. Although these results did not meet the prespecified response criteria, evidence of clinical activity highlights the rationale for further exploration of BET inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway.

PIK3CA and ARID1A mutations in recurrent/metastatic cervical cancer: The NRG Oncology/Gynecologic Oncology Group-0240 National Institutes of Health Beau Biden Cancer Moonshot (LBA 2)

PIK3CA and ARID1A mutations in recurrent/metastatic cervical cancer: The NRG Oncology/Gynecologic Oncology Group-0240 National Institutes of Health Beau Biden Cancer Moonshot (LBA 2)

Molecular landscape and clinical outcomes of ARID1A mutant ovarian and endometrial cancers (2276)

Molecular landscape and clinical outcomes of ARID1A mutant ovarian and endometrial cancers (2276)

Novel insights into the pathogenesis of follicular lymphoma by molecular profiling of localized and systemic disease forms

Knowledge on the pathogenesis of FL is mainly based on data derived from advanced/systemic stages of FL (sFL) and only small cohorts of localized FL (lFL) have been characterized intensively so far. Comprehensive analysis with profiling of somatic copy number alterations (SCNA) and whole exome sequencing (WES) was performed in 147 lFL and 122 sFL. Putative targets were analyzed for gene and protein expression. Overall, lFL and sFL, as well as BCL2 translocation-positive (BCL2+) and –negative (BCL2−) FL showed overlapping features in SCNA and mutational profiles. Significant differences between lFL and sFL, however, were detected for SCNA frequencies, e.g., in 18q-gains (14% lFL vs. 36% sFL; p = 0.0003). Although rare in lFL, gains in 18q21 were associated with inferior progression-free survival (PFS). The mutational landscape of lFL and sFL included typical genetic lesions. However, ARID1A mutations were significantly more often detected in sFL (29%) compared to lFL (6%, p = 0.0001). In BCL2 + FL mutations in KMT2D, BCL2, ABL2, IGLL5 and ARID1A were enriched, while STAT6 mutations more frequently occurred in BCL2- FL. Although the landscape of lFL and sFL showed overlapping features, molecular profiling revealed novel insights and identified gains in 18q21 as prognostic marker in lFL.

Coffin-Siris Syndrome Presents with Novel ARID-2 Gene Mutation

Coffin-Siris Syndrome (CSS) is a rare genetic condition most commonly associated with ARID1A, ARID1B, ARID 2, SMARCA4, SMARCB1, DPF2, and SMARCE1 genetic mutations. The most common features of CSS are intellectual disabilities and facial abnormalities. We report a case of a 10-month-old infant who presented with craniosynostosis and developmental delays. Clinical improvement was observed after conservative therapy. This paper discusses the BAF gene family and how mutations in this gene family influence the development of children. The prognosis of CSS has also been discussed.

Prognostic impact of molecular profiles and molecular signatures in clear cell ovarian cancer

ObjectiveOvarian Clear cell carcinomas (OCCC) are characterized by low response to chemotherapy and a poor prognosis in advanced stages. Several studies have demonstrated that OCCC are heterogenous entities. We have earlier identified four molecular profiles based on the mutational status of ARID1A and PIK3CA. In this study we aimed to examine the association between molecular profiles, Tumor Mutational Burden (TMB), and molecular signatures with the clinical outcome in OCCC MethodsWe identified 55 OCCC cases with corresponding data and biological tissue samples in the Danish Gynecological Cancer Database during 2005-2016. Mutational profiling and TMB were performed using the Oncomine Tumor Mutational Load Assay. Chi-square and Cox regression analyses were used. P-values < 0.05 were considered statistically significant. ResultsMutations in the PIK3CA gene (p=0.04) and low TMB (p=0.05) were associated with disease progression. In multivariate analyses adjusted for stage, patients with tumor mutations in the ARID1A and/or PIK3CA genes had a significantly impaired Progression Free Survival (PFS) and Overall Survival (OS) compared to patients who were wildtype ARID1A and PIK3CA (undetermined subgroup) (HR= 5.42 and HR= 2.77, respectively). High TMB status was associated with an improved PFS (HR= 0.36) and OS (HR= 0.46). A trend towards an improved PFS in patients with APOBEC enrichment was observed (HR 0.45). ConclusionTMB-High was associated with decreased risk of progression and with an improved PFS and OS. Furthermore, OCCC with mutations in either ARID1A and/or PIK3CA genes had a significantly impaired prognosis compared to the undetermined subgroup in stage adjusted analyses.

Racial and sex differences in tumor genomics in urothelial carcinoma

PurposeDifferences in bladder cancer outcomes have been demonstrated by sex and race/ethnicity, with studies showing a higher burden of adverse outcomes among women and racially minoritized populations. Despite these epidemiologic differences, populations with disproportionally adverse outcomes are often underrepresented in genomic cohorts. This exclusion impacts the accuracy and generalizability of genomic studies in bladder cancer and has the potential to widen disparities by sex and/or race/ethnicity. Basic ProceduresWe analyzed pooled somatic mutational data from publicly available cohorts in the cBioPortal open access platform. FindingsA total of 796 unique patients were identified. Average age for the cohort was 67 years (range: 25–98 years), 188 (24%) were female, and the majority were White (n = 423, 85% among those who report race). Median total mutation count was 91 (IQR: 20, 202) per patient. We used multivariable logistic regression to independently evaluate the association between race/sex and mutation status in each of 122 genes of interest, identified from TCGA, adjusting for age and bladder cancer invasive status. In adjusted analyses, male sex was associated with increased risk of mutation in ARID1A, CHD6, and NCOR1 compared with female sex. White race was associated with increased risk of mutation in ARID1A, EP300, PIK3CA, and TP53 and decreased risk of mutation in HRAS compared with non-White race. ConclusionsThese differences highlight the importance of enriching cohorts for female and non-White patients in genomic studies and clinical trials, especially as we test the use of molecular biomarkers to personalize care for patients with bladder cancer.

Characteristics of glioblastomas and immune microenvironment in a Chinese family with Lynch syndrome and concurrent porokeratosis.

Lynch syndrome (LS)-associated glioblastoma (GBM) is rare in clinical practice, and simultaneous occurrence with cutaneous porokeratosis is even rarer. In this study, we analyzed the clinicopathological and genetic characteristics of LS-associated GBMs and concurrent porokeratosis, as well as evaluated the tumor immune microenvironment (TIME) of LS-associated GBMs. Immunohistochemical staining was used to confirm the histopathological diagnosis, assess MMR and PD-1/PD-L1 status, and identify immune cell subsets. FISH was used to detect amplification of EGFR and PDGFRA, and deletion of 1p/19q and CDKN2A. Targeted NGS assay analyzed somatic variants, MSI, and TMB status, while whole-exome sequencing and Sanger sequencing were carried out to analyze the germline mutations. In the LS family, three members (I:1, II:1 and II:4) were affected by GBM. GBMs with loss of MSH2 and MSH6 expression displayed giant and multinucleated bizarre cells, along with mutations in ARID1A, TP53, ATM, and NF1 genes. All GBMs had TMB-H but not MSI-H. CD8+ T cells and CD163+ macrophages were abundant in each GBM tissue. The primary and recurrent GBMs of II:1 showed mesenchymal characteristics with high PD-L1 expression. The family members harbored a novel heterozygous germline mutation in MSH2 and FDPS genes, confirming the diagnosis of LS and disseminated superficial actinic porokeratosis. LS-associated GBM exhibits heterogeneity in clinicopathologic and molecular genetic features, as well as a suppressive TIME. The presence of MMR deficiency and TMB-H may serve as predictive factors for the response to immune checkpoint inhibitor therapy in GBMs. The identification of LS-associated GBM can provide significant benefits to both patients and their family members, including accurate diagnosis, genetic counseling, and appropriate screening or surveillance protocols. Our study serves as a reminder to clinicians and pathologists to consider the possibility of concurrent genetic syndromes in individuals or families.

Gastric cancer with distinct Epstein–Barr virus-positive and -negative tumor components and their whole exome sequencing result: a case Report

BackgroundEpstein–Barr virus (EBV)-associated gastric cancer exhibits distinct clinicopathologic characteristics, showing a good response to immune checkpoint inhibitors and a favorable prognosis. However, gastric cancer comprising distinct EBV-positive and -negative components in a single mass have been rarely reported, and their detailed genetic characteristics have not yet been investigated. Therefore, we reported the case of gastric cancer exhibiting distinct EBV-positive and -negative areas and further investigated its genetic characteristics.Case presentationsA 70-year-old man underwent distal gastrectomy for gastric cancer, which was detected during a routine health check-up. EBV-encoded RNA in situ hybridization revealed distinct EBV-positive and -negative components at each other’s borders, morphologically consistent with collision tumor. We separately sequenced EBV-positive and -negative tumor areas through whole exome sequencing (WES) with matched normal tissue. Remarkably, both EBV-positive and -negative areas shared pathogenic mutations of ARID1A, KCNJ2, and RRAS2. Furthermore, they shared 92 somatic single nucleotide variants and small insertion or deletion mutations, of which 32.7% and 24.5% are EBV-positive and -negative tumor components, respectively.ConclusionsWES results suggested that gastric cancer with distinct EBV-positive and -negative tumor components, formerly categorized as a collision tumor, can be clonally related. EBV-negative tumor component might be associated with loss of EBV during tumor progression.

Genomic determinants in advanced endometrial cancer patients with sustained response to hormonal therapy- case series and review of literature.

The incidence of endometrial cancer is increasing, however treatment options for advanced disease are limited. Hormonal therapy has demonstrated positive outcomes for Stage IV EC. Next generation sequencing (NGS) has increased our understanding of molecular mechanisms driving EC. In this case series, we selected six patients at our institution with Stage IV, hormone receptor positive, endometrial cancer currently being treated with hormonal therapy. All patients achieved SD for at least ≥ 1.5 years. We studied NGS data on all six patients to assess for any common genomic marker which could predict the SD of at least 1.5 years achieved in this group. Institutional Review Board (IRB) approval was obtained from Staten Island University Hospital and Northwell Health, New York. PTEN, PIK3CA, PIK3R1, and ARID1A mutations were found in 83%, 67% 50%, and 67% of patients respectively. TP53 and FGFR2 were both found in 50% of patients. All patients were positive for estrogen and/or progesterone receptor (ER+ and/or PR+). We did not find any one common mutation that could have predicted the observed response (or SD of ≥1.5 years) to hormone therapy. However, our data reflects the prevalence of various mutations reported in literature: (1) Hormone Receptor status is a positive prognostic indicator (2) PTEN/PIK3CA mutations can occur concurrently in EC (3) ARID1A coexists with PTEN (4) FGFR and PTEN pathways may be interlinked. We suggest NGS be employed frequently in patients with endometrial cancer to identify targetable mutations. Additional larger studies are needed to characterize the interplay between mutations.

The epigenetic modifier lysine methyltransferase 2C is frequently mutated in gastric remnant carcinoma.

Gastric remnant carcinoma (GRC), which occurs in the stomach after partial gastrectomy, is a rare and aggressive form of gastric adenocarcinoma (GAC). Comprehensive profiling of genomic mutations in GRC could provide the basis for elucidating the origin and characteristics of this cancer. Herein, whole-exome sequencing (WES) was performed on 36 matched tumor-normal samples from patients with GRC and identified recurrent mutations in epigenetic modifiers, notably KMT2C, ARID1A, NSD1, and KMT2D, in 61.11% of cases. Mutational signature analysis revealed a low frequency of microsatellite instability (MSI) in GRC, which was further identified by MSIsensor, MSI-polymerase chain reaction, and immunohistochemistry analysis. Comparative analysis demonstrated that GRC had a distinct mutation spectrum compared to that of GAC in The Cancer Genome Atlas samples, with a significantly higher mutation rate of KMT2C. Targeted deep sequencing (Target-seq) of an additional 25 paired tumor-normal samples verified the high mutation frequency (48%) of KMT2C in GRC. KMT2C mutations correlated with poor overall survival in both WES and Target-seq cohorts and were independent prognosticators in GRC. In addition, KMT2C mutations were positively correlated with favorable outcomes in immune checkpoint inhibitor-treated pan-cancer patients and associated with higher intratumoral CD3+ , CD8+ tumor-infiltrating lymphocyte counts, and PD-L1expression in GRC samples (p = 0.018, 0.092, 0.047, 0.010, and 0.034, respectively). Our dataset provides a platform for information and knowledge mining of the genomic characteristics of GRC and helps to frame new therapeutic approaches for this disease.

Emerging roles of Aurora-A kinase in cancer therapy resistance.

Aurora kinase A (Aurora-A), a serine/threonine kinase, plays a pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer, including lung cancer, colorectal cancer, and breast cancer. Alteration of Aurora-A impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape and cell death resistance which are involved in cancer progression and resistance. This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance, including chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted therapy resistance (osimertinib, imatinib, sorafenib, etc.), endocrine therapy resistance (tamoxifen, fulvestrant) and radioresistance. Specifically, the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair, feedback activation bypass pathways, resistance to apoptosis, necroptosis and autophagy, metastasis, and stemness. Noticeably, our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1, ARID1A and MYC gene mutation tumors, and potential synergistic strategy for mTOR, PAK1, MDM2, MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase. In addition, we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.

CDK12 alterations and ARID1A mutations are predictors of poor prognosis and therapeutic targets in high-grade salivary gland carcinoma: analysis of the National Genomic Profiling Database.

Due to the diversity of histopathologic types in salivary gland carcinoma, genomic analysis of large cohorts with next-generation sequencing by histologic type has not been adequately performed. We analysed data from 93 patients with salivary duct carcinoma and 243 patients with adenoid cystic carcinoma who underwent comprehensive genomic profiling testing in the Center for Cancer Genomics and Advanced Therapeutics database, a Japanese national genome profiling database. We visualised gene mutation profiles using the OncoPrinter platform. Fisher's exact test, Kaplan-Meier analysis, log-rank test and Cox regression models were used for statistical analysis. In salivary duct carcinoma, a population with CDK12 and ERBB2 co-amplification was detected in 20 of 37 (54.1%) patients with ERBB2 amplification. We identified five loss-of-function variants in genes related to homologous recombination deficiency, such as BRCA2 and CDK12. Cox survival analysis showed that CDK12 and ERBB2 co-amplification is associated with overall survival (hazard ratio, 3.597; P=0.045). In salivary duct carcinoma, NOTCH1 mutations were the most common, followed by mutations in chromatin modification genes such as KMT2D, BCOR, KDM6A, ARID1A, EP300 and CREBBP. In the multivariate Cox analysis, activating NOTCH1 mutations (hazard ratio, 3.569; P=0.009) and ARID1A mutations (hazard ratio, 4.029; P=0.034) were significantly associated with overall survival. CDK12 and ERBB2 co-amplification is associated with a poor prognosis in salivary duct carcinoma. Chromatin remodelling genes are deeply involved in tumour progression in adenoid cystic carcinoma. One such gene, ARID1A, was an independent prognostic factor. In salivary duct carcinoma and adenoid cystic carcinoma, there might be minor populations with mutations that could be targeted for treatment with the synthetic lethality approach.

Mutational spectrum for guiding the decision of adjuvant treatment in patients with resected biliary tract carcinoma.

Systemic chemotherapy or chemoradiation therapy has proven to be effective in treating advanced biliary tract carcinoma (BTC). However, its efficacy in the adjuvant setting remains controversial. Therefore, this study aimed to determine the prognostic significance of genomic biomarkers in resected BTC and their potential role in stratifying patients for adjuvant treatment. We retrospectively reviewed 113 BTC patients who underwent curative-intent surgery and had available tumor sequencing data. Disease-free survival (DFS) was the primary outcome examined and univariate analysis was used to identify gene mutations with prognostic value. Favorable and unfavoratble gene subsets were distinguished from the selected genes through grouping, respectively. Multivariate Cox regression was used to identify independent prognostic factors of DFS. Our results indicated that mutations in ACVR1B, AR, CTNNB1, ERBB3, and LRP2 were favorable mutations, while mutations in ARID1A, CDKN2A, FGFR2, NF1, NF2, PBRM1, PIK3CA, and TGFBR1 were unfavorable mutations. In addition to age, sex, and node positive, favorable genes (HR = 0.15, 95% CI = 0.04-0.48, p = 0.001) and unfavorable genes (HR = 2.86, 95% CI = 1.51-5.29, p = 0.001) were identified as independent prognostic factors for DFS. Out of the 113 patients, only 35 received adjuvant treatment whereas the majority (78) did not. For patients with both favorable and unfavorable mutations undetected, adjuvant treatment showed negative effect on DFS (median DFS: S441 vs. 956 days, p = 0.010), but there was no significant difference in DFS among those in other mutational subgroups. Genomic testing might be useful in guiding the decisions regarding adjuvant treatment in BTC.

Genomic characterization between HER2-positive and negative gastric cancer patients in a prospective trial.

We aimed to clarify the genomic characteristics of HER2-positive and negative gastric cancer cases that potentially affect tumor progression and treatment response in a prospective trial. We collected 80 formalin-fixed paraffin-embedded (FFPE) samples (49 HER2+ and 31 HER2-) from gastric cancer patients who participated in the TROX-A1 trial (UMIN000036865). We queried a 435-gene panel (CANCERPLEX-JP) to generate comprehensive genomic profiling data, including the tumor mutation burden, somatic mutations, and copy number variations. In addition, the genomic differences between HER2+ and HER2- gastric cancer patients were analyzed. Mutational analyses showed that TP53 was the most frequently mutated gene regardless of HER2 status. ARID1A mutation was significantly enriched in HER2-negative patients. The number of total mutations in HER2-negative patients with ARID1A mutation was remarkably higher than that in HER2-positive patients. Next, copy number variation analyses showed that the number of amplified genes (such as CCNE1, PGAP3, and CDK12) in HER2-positive cases was significantly higher than that in HER2-negative cases. Moreover, PTEN deletion was more common in HER2-positive cases. Finally, we found that, compared with HER2-positive patients, HER2-negative patients tended to have a higher tumor mutation burden, particularly in patients with ARID1A mutation. Pathway analyses of the gene alterations showed an enrichment of several immune-related pathways in HER2-negative patients. According to the genomic profiling of HER2-positive and negative gastric cancer, several gene alterations in the HER2 pathway may be the potential mechanism underlying trastuzumab resistance. Relative to HER2-positive gastric cancer, HER2-negative gastric tumors with ARID1A mutation may be sensitive to immune checkpoint inhibitors.

Identification of New Potential Prognostic and Predictive Markers in High-Grade Osteosarcoma Using Whole Exome Sequencing.

Conventional high-grade osteosarcoma (OS) is the most common primary cancer of bone and it typically affects the extremities of adolescents. OS has a complex karyotype, and molecular mechanisms related to carcinogenesis, progression and resistance to therapy are still largely unknown. For this reason, the current standard of care is associated with considerable adverse effects. In this study, our aim was to identify gene alterations in OS patients using whole exome sequencing (WES) to find new potential prognostic biomarkers and therapeutic targets. We performed WES on formalin-fixed paraffin-embedded (FFPE) biopsy materials collected from 19 patients affected by conventional high-grade OS. The clinical and genetic data were analyzed according to response to therapy, presence of metastasis and disease status. By comparing good and poor responders to neoadjuvant therapy, we detected a clear prevalence of mutations in the ARID1A, CREBBP, BRCA2 and RAD50 genes in poor responders that negatively influence the progression-free survival time. Moreover, higher tumor mutational burden values correlated with worse prognosis. The identification of mutations in ARID1A, CREBBP, BRCA2 and RAD50 may support the use of a more specific therapy for tumors harboring these alterations. In particular, BRCA2 and RAD50 are involved in homologous recombination repair, and could thus be used as specific therapy targets of inhibitors of the enzyme Poly ADP Ribose Polymerase (PARP). Finally, tumor mutational burden is found to be a potential prognostic marker for OS.

The clinical feasibility of circulating tumor DNA alterations in patients with advanced hepatocellular carcinoma.

4110 Background: Need for individualized treatment based on tumor attributes is being reinforced with the rapid development of targeted therapies and immune checkpoint inhibitors for hepatocellular carcinoma (HCC). Lack of mandatory tissue biopsy for the diagnosis of HCC, continues to be a challenge for development of precision medicine for HCC compared to other solid tumors. Liquid biopsy enables comprehensive genomic profiling of circulating tumor DNA (ctDNA) shed from tumors into the circulation. This could compensate for the lack of tissue-based analysis in HCC providing a non-invasive and safer option for genomic profiling. This study aims to address the concordance between commercially available ctDNA and tissue genomic profiling in patients with advanced HCC and to assess the feasibility of liquid biopsy in the treatment of patients with HCC. Methods: Patients subjected to tissue-based next-generation sequencing (NGS) before systemic therapy for advanced HCC at CHA Bundang Medical Center from June 2020 to October 2022 and also had sufficient plasma samples available for ctDNA analysis were included. Oncomine Comprehensive Assay (OCA) ThermoFisher was used for tissue-based NGS and Guardant360 for ctDNA based NGS. For the concordance assessment for the same patient, paired samples of ctDNA and tumor tissue, we investigated the common targeted regions across both the panels. Results: Out of hundred thirty patients included in this study, 98% percent of ctDNA samples for these patients were successfully sequenced; ctDNA were detected in 88% of the samples. For the assessment of concordance between intra-patient ctDNA and tumor tissues, we investigated only clinically important (AMP/ASCO/CAP guidelines tier 1 or 2) variants. When we considered the variants detected in tissues as true positive, the concordance between the mutations detected from ctDNA and tissue samples indicated 68.9% sensitivity and 63.1% positive predictive value (PPV). In ctDNA, targetable alterations were detected in 16.9% of samples, such as ARID1A mutations (7.7%), PTEN mutations (6.9%), PIK3CA hotspot mutations (1.5%), RAS mutations (1.5%), and one RET fusion (0.8%). Regarding the concordance between ctDNA and tumor tissue, the sensitivity for mutation was high for RAS mutation (100.0%), PTEN mutations (100.0%), and ARID1A mutations (75.0%) but low for PIK3CA hotspot mutations (0.0%). One RET fusion was identified only in ctDNA. Conclusions: ctDNA-based genotyping demonstrated clinically acceptable concordance with tissue genomic profiling in patients with advanced HCC. Thus, liquid biopsy using ctDNA help address any challenges associated with the limited use of tissue-based genomic profiling in HCC. Investigation of time between blood and tissue collection and the impact it has on concordance is ongoing.

EZH2/EZH1 inhibitor tulmimetostat (CPI-0209) in patients with advanced solid tumors or hematologic malignancies: Preliminary phase II results.

3094 Background: Many preclinical tumor models with mutations in ARID1A and BAP1 are highly sensitive to EZH2 inhibition. Tulmimetostat (CPI-0209) is an investigational oral, next-generation, dual EZH2/EZH1 inhibitor with durable target coverage. Phase I dose escalation established a recommended Phase II dose of 350 mg (Lakhani et al. ASCO 2021). We report preliminary Phase II findings from the ongoing Phase I/II study (NCT04104776). Methods: Phase II is evaluating tulmimetostat 350 mg once daily in 28-day cycles in 6 disease-based cohorts (Table). The Simon 2-stage study design requires 1 response (complete [CR] or partial [PR]) in stage 1 (n = 10 patients [pts]) for expansion to stage 2 (plus n = 19) (except in M4, see table). Primary endpoint is objective response rate (ORR) based on disease-specific criteria; secondary objectives include safety. Results: As of Nov 08, 2022, 62 pts received ≥1 dose (safety evaluable); 48 had ≥1 postbaseline tumor assessment (efficacy evaluable). Pts had median 3.2 years (0.6–19.6) since diagnosis; 77.4% had ≥2 prior lines of therapy. Cohorts M2, M5 and M6 had completed stage 1 enrollment. At cut-off, best responses among evaluable patients (Table) show 4 cohorts have at least 1 confirmed response, including 2 CR and 1 PR in 7 pts with peripheral T-cell lymphoma (PTCL). 47 pts (75.8%) experienced TEAEs leading to dose modifications, 20 (32.3%) had serious TEAEs, and 5 (8.1%) discontinued treatment due to TEAEs. The most frequent TEAEs (≥15% of pts) (any Grade/Grade ≥3) considered at least possibly related to tulmimetostat were thrombocytopenia (51.6%/27.4%), diarrhea (45.2%/12.9%), nausea (37.1%/0%), anemia (30.6%/16.1%), fatigue (29.0%/0%), alopecia (25.8%/1.6%), dysgeusia (24.2%/0%), vomiting (21.0%/0%), and neutropenia (17.7%/14.5%). Conclusions: Based on response criteria of ORR ≥1/10 pts, the ovarian (M2), endometrial (M3), and mesothelioma (M5) cohorts achieved eligibility for stage 2 expansion (not relevant in M4). The safety profile of tulmimetostat is consistent with EZH2 inhibition and previous data. These preliminary findings in heavily pretreated pts with multiple tumor types, including tumors with ARID1A alterations or BAP1 loss, support ongoing investigation of tulmimetostat. Clinical trial information: NCT04104776 . [Table: see text]

Genome sequencing-based prognosis, mutational analysis, and survival rate of clear cell renal cell carcinoma.

e16543 Background: The clear cell renal cell carcinoma (ccRCC) is the most prevalent genitourinary cancer, and carries a poor prognosis. Information regarding whole genome sequencing, a prognostic prediction system, and overall survival in ccRCC is limited. While loss of VHL is commonly implicated in ccRCC, two genes indicated in other cancers, SDHD and ARID1A, have limited literature on their correlation to ccRCC. Hence, we aimed to analyze the genomic profile, epidemiological characteristics and overall survival of ccRCC. Methods: We utilized cBioPortal cancer genomics [The Cancer Genome Atlas (TCGA) PanCancer Atlas, TCGA Firehose Legacy, and TCGA Nature 2013] to study the genetic mutations associated with ccRCC. Epidemiological characteristics and genetic profiles were evaluated, and a query was generated to calculate 5 year and 10 year survival rate with the most common mutations. Log-rank test and Kaplan–Meier estimator were used in analyzing the survival function. Patients with two or more overlapping mutations (72) were excluded. Results: We identified 761 patients with ccRCC, out of which 442 had primary ccRCC with all demographic details available. 65.8% were males, 58.1% were Caucasian, and 7.2% were African American. Majority of patients (199) were between the ages of 50-65 years. 286 (64.7%) were alive and 156 (35.3%) were deceased. The common mutations associated with reduced survival were VHL, BAP1, SDHA, SDHD, and ARID1A. Median survival of patients with VHL, BAP1, SDHA, SDHD, ARID1A mutations was 118.85, 93.04, 40.70, 2.04, and 6.02 months respectively in comparison with unaltered mutation group (78.44 months) (p &lt; 0.0001). (Table 1) Survival was lowest amongst SDHD [2.04 months] and ARID1A [6.02 months]. (p = 3.26e-10). In survival analysis, SDHD and ARID1A were associated with lowest survival after initial diagnosis at 60 months (Figure 1) and 120 months (Figure 2). (p = 2.592e-3). Conclusions: Our study found that SDHD, ARID1A, and SDHA genes were associated with the worst prognosis in ccRCC with median survival of 2.04, 6.02, and 40.70 months. This study may provide insight for targeted therapies for ccRCC and improve the prognosis of these patients. [Table: see text]

The genomic, transcriptomic, and immunological landscape of TROP2 in solid tumors.

3118 Background: TROP2 expression is associated with decreased overall survival in colorectal and pancreatic cancers. The antibody drug conjugate sacituzumab delivers a SN38 toxic payload to TROP2-expressing cells and is approved for the treatment of breast cancer and urothelial carcinoma. We aimed to explore the genomic and immunological landscape of TACSTD2 (TROP2-encoding gene) in different solid tumors. Methods: Tumors from breast cancer (BC, N=11,246), colorectal carcinoma (CRC, N= 15,425), liver cancer (LC, N=433), pancreatic cancer (PC, N=5,488) and urothelial carcinoma (UC, N=5,488) were assessed at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). PD-L1 (SP142; Positive (+): ≥2+, ≥5%) expression was assessed by IHC. When investigating the genomic landscape, mutation prevalence was calculated for pathogenic SNVs/indels. TACSTD2-High (H) and -Low (L) expression was defined as top and bottom quartile of TACSTD2 transcripts per million, respectively. A transcriptomic signature predictive of response to immunotherapy was applied (T cell-inflamed score [Bao, 2020]). tests were applied as appropriate, with P-values adjusted for multiple comparisons ( p &lt; .05). Real-world overall survival data was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients. Results: Compared to TACSTD2-L, TACSTD2-H tumors had a higher prevalence of TP53 mutations in BC ( TACSTD2-H 59% vs -L 48%), CRC (77% vs 71%), LC (43% vs 23%) and PC (83% vs 69%), whereas UC TACSTD2-H had a lower prevalence (54% vs 67%, p &lt; .05 for all). TACSTD2-H tumors had a higher rate of KRAS mutations in CRC (55% vs 38%, p &lt; .05) and PC (96% vs 78%, p &lt; .05). In CRC, the percentage of KRAS mutations that were G12C was higher in TACSTD2-H (7.3% vs 6.4%, p &lt; .05). TACSTD2-H tumors had a higher rate of ARID1A mutations in CRC (6.7% vs 10%, p &lt; .05) and UC (29 vs 20%, p &lt; .05). A higher prevalence of PD-L1+ tumors was observed in CRC TACSTD2-H (6.4 vs 3.9%, p &lt; .05) and the opposite pattern was observed in UC (16% vs 37%, p &lt; .05). TACSTD2-H tumors were more frequently T cell-inflamed across investigated cancers (BC: TACSTD2-H 36% vs -L 19%, CRC: 29% vs 14%, LC: 54% vs 10%, PC: 42% vs 20%, UC: 32% vs 28%, all p &lt; .05). TACSTD2-H was associated with worse overall survival in PC (HR 1.31 [1.19-1.44], p &lt; .001), BC (HR 1.13 [1.03-1.23], p &lt; .007) and CRC (HR 1.33 [1.24-1.42], p &lt; .001), while this association was not observed in UC (HR .98 [.86-1.12], p = .75) or LC (HR 1.14[.82-1.57], p = .44). Conclusions: The association of TACSTD2 expression with KRAS, TP53 and ARID1A mutations and T cell-inflamed tumors (ICI responsive) should be considered as possible combination therapies with TROP2 targeting antibody drug conjugates are investigated.